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Ligands for monoamine receptors and transporters, and methods of use thereof |
| 7517892 |
Ligands for monoamine receptors and transporters, and methods of use thereof
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| Patent Drawings: | |
| Inventor: |
Aquila, et al. |
| Date Issued: |
April 14, 2009 |
| Application: |
09/951,130 |
| Filed: |
September 12, 2001 |
| Inventors: |
Aquila; Brian M. (Marlborough, MA)
Bannister; Thomas D. (Northborough, MA)
Cuny; Gregory D. (Somerville, MA)
Hauske; James R. (Concord, MA)
Holland; Joanne M. (Brookline, MA)
Persons; Paul E. (Westborough, MA)
Radeke; Heike (South Grafton, MA)
Wang; Fengjiang (Northborough, MA)
Shao; Liming (Lincoln, MA)
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| Assignee: |
Sepracor Inc. (Marlborough, MA) |
| Primary Examiner: |
Coleman; Brenda L |
| Assistant Examiner: |
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| Attorney Or Agent: |
Day; Jones |
| U.S. Class: |
514/317; 514/321; 514/323; 514/326; 514/327; 514/330; 514/331; 546/197; 546/201; 546/207; 546/216; 546/225; 546/229; 546/237; 546/238; 546/240; 546/336 |
| Field Of Search: |
514/317; 514/321; 514/323; 514/326; 514/327; 514/330; 514/331; 546/197; 546/201; 546/207; 546/216; 546/225; 546/229; 546/236; 546/237; 546/238; 546/240 |
| International Class: |
A61P 25/00; A61K 31/445; C07D 211/00; C07D 401/00 |
| U.S Patent Documents: |
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| Foreign Patent Documents: |
0 000 693; 0 076 089; 0 080 940; 0 138 716; 0 190 496; 0 229 623; 0 266 574; 0 290 958; 0 639568; 0 649 838; 1.221.294; 2 248 049; 2 471 378; 2 534 915; 2 553 411; 2 564 462; 1138405; 1184023; 1 260 886; 1 382 526; 1 382 965; 1 452 701; 1 501 321; 11-269172; 111542; WO 91/09032; WO 92/01672; WO 92/02502; WO 93/15052; WO 94/13291; WO 95/03302; WO 95/25732; WO 95/33722; WO 95/33723; WO 98/51668; WO 99/65487; WO 00/09491; WO 00/71518; WO 01/32178; WO 01/68604; WO 01/92226 |
| Other References: |
Balsamo et al., 3-[(2-Ethoxyphenoxy)methyl]piperidine Derivatives. Synthesis and Antidepressant Activity, Journal of Medicinal Chemistry, vol.30, No. 1, pp. 222-225, Jan. 1987. cited by examiner.
Jones et al, The Medical Benefit of 5-HT Research, Pharmacology, Biochemistry and Behavior, vol. 71, No. 4, Apr. 2002, pp. 555-568. cited by examiner.
Denton et al., Antispasmodics. VI. Additional Substituted Beta Amino Ketones, Journal of the American Chemical Society, 1950, vol. 72, pp. 3792-3794. cited by examiner.
Helsley et al., Piperidylalkylindoles. 1. Hypotensive Activity of 3-[2-(Phenoxypiperidyl)ethyl]indoles, Journal of Medicinal Chemisty, vol. 21, No. 3, pp. 309-312, 1978. cited by examiner.
Engelstoft and Hansen; "Synthesis and 5HT Modulating Activity of Stereoisomers of 3-Phenoxymethyl-4-Phenylpiperidines", Acta Chemica Scandinavica 50: 164-169, (1996). cited by other.
O'Neill et al.; "Effect of Ca2+ and Na+ Channel Inhibitors in Vitro and in Global Cerebral Ischaemia in Vivo", European Journal of Pharmacology 332: 121-131, (1997). cited by other.
International Search Report Completed on Feb. 27, 2002 and Mailed on Mar. 13, 2002. cited by other.
Andersson et al., 2001, CAS: 135:242140. cited by other.
Brown et al., 1990, CAS: 112:35578. cited by other.
Kutsuki et al., 1990, CAS: 112:7383. cited by other.
Nagahara et al., 1994, CAS: 120:323168. cited by other. |
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| Abstract: |
One aspect of the present invention relates to heterocyclic compounds. A second aspect of the present invention relates to the use of the heterocyclic compounds as ligands for various mammalian cellular receptors, including dopamine, serotonin, or norepinephrine transporters. The compounds of the present invention will find use in the treatment of numerous ailments, conditions and diseases which afflict mammals, including but not limited to addiction, anxiety, depression, sexual dysfunction, hypertension, migraine, Alzheimer's disease, obesity, emesis, psychosis, schizophrenia, Parkinson's disease, inflammatory pain, neuropathic pain, Lesche-Nyhane disease, Wilson's disease, and Tourette's syndrome. An additional aspect of the present invention relates to the synthesis of combinatorial libraries of the heterocyclic compounds, and the screening of those libraries for biological activity, e.g., in assays based on dopamine transporters. |
| Claim: |
We claim:
1. A compound is represented by A: ##STR00280## wherein X represents CH.sub.2; Z represents O; m is 2; n is 1; y is 1; R.sub.1 is 4-trifluoromethylphenyl or3,4-methylenedioxyphenyl; R.sub.3 is H; R.sub.4 is 4-chlorophenyl; R.sub.5 and R.sub.6 are selected independently for each occurrence from the group consisting of H and alkyl; R.sub.8 and R.sub.9 are each H; any two instances of R.sub.5 and R.sub.6may be connected through a covalent bond; and the stereochemical configuration at any stereocenter of a compound represented by A is R, S, or a mixture of these configurations.
2. A compound is represented by A: ##STR00281## wherein X represents CH.sub.2; Z represents O; m is 3; n is 1; y is 1; R.sub.1 is 4-trifluoromethylphenyl or 3,4-methylenedioxyphenyl; R.sub.3 is H; R.sub.4 is 4-chlorophenyl; R.sub.5 andR.sub.6 are selected independently for each occurrence from the group consisting of H, OH and alkyl; R.sub.8 and R.sub.9 are each H; any two instances of R.sub.5 and R.sub.6 may be connected through a covalent bond; and the stereochemicalconfiguration at any stereocenter of a compound represented by A is R, S, or a mixture of these configurations.
3. The compound of claim 1, wherein said compound is a single stereoisomer.
4. The compound of claim 2, wherein said compound is a single stereoisomer.
5. A composition, comprising a compound of claim 1; and a pharmaceutically acceptable excipient.
6. A composition, comprising a compound of claim 2; and a pharmaceutically acceptable excipient.
7. A method of treating a mammal suffering from addiction, anxiety, depression, sexual dysfunction, hypertension, migraine, Alzheimer's disease, obesity, emesis, psychosis, analgesia, schizophrenia, Parkinson's disease, restless leg syndrome,sleeping disorders, attention deficit hyperactivity disorder, irritable bowel syndrome, premature ejaculation, menstrual dysphoria syndrome, urinary incontinence, inflammatory pain, neuropathic pain, Leschye-Nyhane disease, Wilson's disease, orTourette's syndrome, comprising the step of: administering to said mammal a therapeutically effective amount of a compound of claim 1.
8. The method of claim 7, wherein said mammal is a primate, equine, canine or feline.
9. The method of claim 7, wherein said mammal is a human.
10. The method of claim 7, wherein said compound is administered orally.
11. The method of claim 7, wherein said compound is administered intravenously.
12. A method of treating a mammal suffering from addiction, anxiety, depression, sexual dysfunction, hypertension, migraine, Alzheimer's disease, obesity, emesis, psychosis, analgesia, schizophrenia, Parkinson's disease, restless leg syndrome,sleeping disorders, attention deficit hyperactivity disorder, irritable bowel syndrome, premature ejaculation, menstrual dysphoria syndrome, urinary incontinence, inflammatory pain, neuropathic pain, Leschye-Nyhane disease, Wilson's disease, orTourette's syndrome, comprising the step of: administering to said mammal a therapeutically effective amount of a compound of claim 2.
13. The method of claim 12, wherein said mammal is a primate, equine, canine or feline.
14. The method of claim 12, wherein said mammal is a human.
15. The method of claim 12, wherein said compound is administered orally.
16. The method of claim 12, wherein said compound is administered intravenously. |
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